1. Field of the Invention
The present invention relates to a method for preparing a non-fibrous porous material being swellable but not soluble in water essentially consisting of one or more hydrophilic polymers and/or pharmaceutical water-soluble medicaments, an absorbing article containing such material and the use of such material for the preparation of an absorbing article.
2. Description of the Related Art
Non-fibrous porous materials essentially consisting of one or more hydrophilic polymers and/or pharmaceutical water-soluble medicaments and methods for preparing such materials are disclosed in WO 95/05204 and in JP 01-011141.
One method for preparing such products using a hydrous solution of a hydrophilic polymer such as casein, gelatine, collagen, albumin, fibroin, cellulose, starch, agar, sodium carboxyl methyl cellulose, methyl cellulose, polyvinyl alcohol, polyacrylic acid, or polyacrylamide is disclosed in JP 01-011141. According to JP 01-011141, a surfactant of non-ionic, cationic, anionic or amphoteric type is added to the hydrous solution and then freeze-drying is carried out. The polymer is dispersed in water at a concentration of 0.05 to 50%, and the surfactant is used in amounts of from 0.5-100%.
Another method or preparing such products using a hydrous solution of a hydrophilic polymer such as a synthetic hydrophilic polymer, a polysaccharide or a biological hydrophilic polymer is disclosed in WO 95/05204. According to WO 95/05204, one or more pharmaceutical medicaments and/or hydrophilic polymers are dissolved in water to provide a solution or a sol, a freeze plate is pre-nucleated by passive condensation or by evaporating or atomising water or the aqueous solution of the pharmaceutical medicaments and/or hydrophilic polymers and/or salts, the solution of one or more pharmaceutical medicaments and/or hydrophilic polymers is provided on the pre-nucleated freeze plate, the temperature of which is kept below the freezing point of the atomised water or solution, the solution is frozen to provide an ice sheet comprising the pre-nucleated frozen material, the sheet is freeze dried, and the resulting sheet is optionally cut into pieces of suitable sizes.
WO 96/20015 discloses chitosan salts and a process for the preparation thereof. The chitosan salt may be recovered in a desired form depending on the use for which it is intended, and for use in absorbent personal care products such as a wound dressing it is generally in the form of a discrete particle, fibre or flake. There is no indication of production of a cohesive gel and the content of cross-linker is below 10 weight percent.
GB 2 296 250 discloses a method for-preparing water-swellable, water-insoluble chitin/chitosan salts having improved absorption properties by forming a mixture of a chitosan, water, an acid, and, optionally, a crosslinking agent, recovering the formed chitosan salt from the mixture and, optionally, treating said recovered chitosan salt with heat under humid conditions. Freeze drying of these hydrogels results in stiff and brittle xerogels which are unpleasant in contact with human skin or wounds.
A water absorbing porous material can be prepared from cross-linked CMC powders by the freeze drying technique disclosed in WO 95/05204. However, xerogels produced in this manner have no cohesion after rehydration due to the formation of a sol gel.
These properties render such materials less suitable for use if they are not fully enclosed as they tend to disintegrate when absorbing water. Such disintegration render such materials less suitable for use in wound dressings as it is highly desirable that the absorbing material has a sufficient cohesion to be removed as an integrate piece without leaving residues on the skin or in the wound.
WO 94/04724 discloses a method of producing a fibre or film by extruding an aqueous solution of a water-soluble polymer into a gaseous medium to form fibre or film. The extruded fibre or film is dried and cross-linked at a temperature in the range of 125 to 250xc2x0 C. to a degree sufficient that the crosslinked fibre or film is water-insoluble. The resulting fibres or film are intended for use in preparing webs for use in absorbing articles.
EP 0 269 393 discloses preparation of fibre or film by dry extrusion of a solution of a linear polymer formed from a water soluble blend of mono ethylenically unsaturated monomers comprising plasticizing monomer.
EP 0 268 498 discloses a water absorbent water insoluble polymeric element such as a fibre, film, coating, bonding layer or foam made by forming a substantially linear polymer by polymerization of water soluble ethylenically unsaturated monomer blends and then crosslinking the same.
DE 26 27 708 discloses water swellable fibres made from water-insoluble acrylic acid polymerization.
The above references are silent with respect to preparation of an absorbing material having a very high absorbing capacity and having, at the same time, a very high degree of cohesion rendering the material suitable for use in an article being in direct contact with the skin or the surface of a wound
Thus, there is still a need for an absorbing material having a very high absorbing capacity and having, at the same time, having a very high degree of cohesion rendering the same suitable for use in an article being in direct contact with the skin or the surface of a wound. Examples of absorbing articles are, e.g., disposable diapers, incontinence articles, sanitary napkins or the like having an absorbing core or an absorbing wound dressing.
It has surprisingly been found that the novel porous materials prepared according to the present invention are swellable but not soluble in water and are very suitable for use as absorbing components in, e.g., wound dressings.
The present invention relates to a method for preparing a non-fibrous porous material being swellable but not soluble in water essentially consisting of one or more hydrophilic polymers and/or pharmaceutical water-soluble medicaments; a non-fibrous material which may be produced by the method; a dressing comprising a non-fibrous porous material essentially consisting of one or more hydrophilic polymers and/or pharmaceutical medicaments; and the use of such a material for the preparation of a dressing or an absorbent article.
In a first aspect, the invention relates to a method for preparing a non-fibrous porous material being swellable but not soluble in water, the material essentially consisting of one or more natural or semi-synthetic hydrophilic polymers or one or more hydrophilic polymeric component(s) and one or more pharmaceutical medicaments, the method comprising forming an aqueous solution or sol gel comprising one or more hydrophilic polymers or one or more hydrophilic polymeric component(s) and one or more pharmaceutical medicaments, forming an object of the solution or sol gel having a desired shape and dehydrating the same leaving a non-fibrous porous material in a solid, porous form, and subjecting the resulting porous material to a dry heat treatment.
A material produced in this manner shows superior absorbing capacity and does not disintegrate upon absorbing water. It is believed that the dry heat treatment causes formation of cross-links in the non-fibrous porous material being responsible for the superior properties with respect to absorbing capacity combined with a cohesion ensuring non-disintegration upon swelling.
In a preferred embodiment of the method of the invention, one or more hydrophilic polymeric component(s) or one or more hydrophilic polymeric materials component(s) and one or more pharmaceutical medicaments are dissolved or solubilized in water to provide a sol gel, the gel sol is placed on a surface, the temperature of which is to be kept below the freezing point of water or the gel sol, freezing the solution or sol gel to provide an ice structure comprising the frozen material and removing the water selectively leaving the solid materials of the solution or sol gel in the form of a porous structure and subjecting the resulting porous material to a dry heat treatment.
It is especially preferred that the freeze plate is pre-nucleated and that the sol gel is placed on the pre-nucleated freeze plate which enables a fine control of the structure of the frozen ice structure.
In accordance with the invention, the water may preferably be removed by freeze-drying or by solvent extraction.
When carrying out the heat treatment in the method of the invention, the process may be allowed to proceed at a relatively longer time at a low temperature or a relatively shorter time at an elevated temperature. It is preferred to keep the material at an elevated temperature of from 40 to 220xc2x0 C. for a period of from 1 minute to several hours. The temperature is preferably held at from 50 to 70xc2x0 C. for at least 15 minutes.
The final heat treatment causes a xe2x80x9csecondary crosslinkingxe2x80x9d. The secondary crosslinking can occur in the step where the solvent is removed (in the freeze-drying process or if the water removed by evaporation).
Such a material shows a superior absorbing capacity and provides a coherent gel which does not disintegrate upon absorbing water is and may be removed after use as a whole.
In one preferred embodiment of the invention the material comprises two or more hydrophilic polymers and optionally pharmaceutical medicaments comprising polyionic/polyfunctional materials having opposite charges.
This means, that at least two polymers in the material must have opposite charges, but the material could for example comprise one cationic polymer, two anionic polymers and one pharmaceutical medicament. Optionally, the material could comprise polymer components having the same di-, tri or oligomer component of the opposite charge.
It is preferred to use a polyionic/polyfunctional anionic material comprising at least one polyanionic group such as: sulphates, thiosulphates, acids, acid salts or phosphates or functional groups such as acid chlorides or anhydrides, and at least one polycationic group such as a primary, secondary or tertiary amine or phosphine group. One of two polymer components could also be a pharmaceutical medicament having an ionic charge. Another option is that at least one of the materials is amphoteric (such as some polypeptides and amino acids).
The polymers are dissolved forming aqueous solutions. Normally, a cationic polymer needs an acid in order to be dissolved, but if the cationic polymer is present in the form of a salt, it is normally soluble in water. For example, chitosan is only soluble in water when an acid is present (the acid protonates chitosan), whereas chitosan lactate (which is protonated) is directly soluble in water. An anionic polymer is normally present in the form of a salt and is therefore dissolved in water. For example, instead of using the insoluble alginic acid, an alginate is used (alginate is the salt of alginic acid). If the anionic polymer is alginic acid, it is dissolved by converting it into a salt by dissolving it in a basic aqueous solution.
Thus, a polymer may be converted from a non-ionic (and insoluble) state to cationic (and soluble) state by addition of acid. One specific example of such a material is, e.g., chitosan.
Acids used to dissolve a cationic polymer could be any lower carboxylic acid having from 1 to 7 carbon atoms preferably 1 to 4 carbon atoms. The organic acid could be both mono-, di or trivalent acids such as formic acid, acetic acid, glycolic acid, glyoxylic acid, propionic acid, acrylic acid, butyric acid, pyruvic acid, oxalic acid or lactic acid.
If the cationic polymer is dissolved as a salt, where the counter ion is inorganic (for example chitosan chloride), which is water soluble (no addition of acid is necessary to dissolve the cationic polymer), one could add (dissolve) to the cationic polymer solution (or to the anionic polymer solution before mixing or to the mixed dispersion) some organic acid salt such as sodium acetate, which enables a secondary crosslinking. When the cationic polymer is a salt with an inorganic counter ion, there is however also another option. Instead of adding an organic acid salt one could add a low molecular weight amine or ammonia. For example, if chitosan chloride (cationic) is dissolved in water, ammonia could be added to this solution (or to the anionic polymer solution before mixing or to the mixed dispersion).
At last the cationic polymer could be present as a salt, where the counter ion is organic such as chitosan lactate, which is soluble in water and the lactate ion enables the secondary crosslinking. In this situation no addition of any molecule should be necessary. The organic counter ion could be any carboxylic acid salt having from 1 to 7 carbon atoms such as formic acid, acetic acid, glycolic acid, glyoxylic acid, propionic acid, propenoic acid, butyric acid, pyruvic acid, oxalic acid or lactic acid.
Thereafter, the solutions are mixed forming a gel dispersion. When the solutions are mixed, the anionic groups of the anionic polymer combine with the cationic groups of the cationic polymer forming a crosslinking between the two polymers. This reaction is in the present context designated xe2x80x9cprimary crosslinkingxe2x80x9d. Normally this reaction occurs momentarily when the solution is mixed. By continuing the mixing, the solution is turned into a dispersion or a xe2x80x9csol gelxe2x80x9d. The mixing time may vary from a few seconds to several minutes for obtaining a xe2x80x9chomogeneousxe2x80x9d dispersion. The mixing process may be any convenient mixing process known per se capable of forming a dispersion or a sol gel.
When a xe2x80x9chomogeneousxe2x80x9d dispersion/sol gel is obtained, it is frozen, solvent removed and heat treated as described earlier in the detailed description of the invention. xe2x80x9cSecondary crosslinkingxe2x80x9d during in the heat treatment. Such crosslinking may be effected by establishing ionic links between the polymeric chains or by establishing of covalent bonds, e.g., by formation of ester bonds by cleavage of water from carboxylic and hydroxylic groups forming ester groups.
xe2x80x9cSecondary crosslinkingxe2x80x9d can occur when at least two polyionic/polyfunctional materials having opposite charges are present, at least 15% by weight of the polyionic/polyfunctional materials have the same charge. The term xe2x80x9cpolyxe2x80x9d is used in the present context to designate at least two units.
It is also an aspect of the invention to have two different natural or semi-synthetic hydrophilic polymers or polymeric component(s) having opposite functionality/charge in any desired ratio from 15:85 to 85:15, more preferably form 20:80 to 80:20.
In a further embodiment of the invention, a pharmaceutical medicament may participate in the crosslinking process as one of the parts as long as such crosslinking does not have any adverse effect on the pharmaceutical effect thereof.
In accordance with the invention, the multifunctional/ionic component enabling crosslinking preferably is present in an amount of from 20 to 100% by weight. It is often preferred to combine two hydrophilic polymers in a proportion by weight of from 40:60 to 60:40.
Such a material also shows a superior absorbing capacity and provides a coherent gel which does not disintegrate upon absorbing water and may be removed after use as a whole.
Examples of anionic groups linked to an anionic polymer which may be used for the invention and which may undergo xe2x80x9csecondary crosslinkingxe2x80x9d with a polymer of opposite charge are groups such as sulphates or thiosulphates, acids or acid salts such as alginates or phosphates or functional groups such as acid chlorides or anhydrides.
Cationic groups linked to a cationic polymer may, e.g., be amines, phosphines or imines. The amine groups may be primary, secondary or tertiary alkyl, cycloalkyl or aromatic amines. The term xe2x80x9calkylxe2x80x9d is used in the present context to designate straight or branched alkyl groups having up to 6 carbon atoms, preferably 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, a butyl, a isobutyl, an pentyl or hexyl group. Cycloalkyl may comprise from 5 to 7 carbon atoms. An example of an aromatic amine is phenylamine.
The best results are achieved when using sulphates, acids, acid salts or phosphates as anionic groups and primary amine groups as cationic groups attached directly to a polymer backbone, preferably a polysaccharide.
The materials comprising anionic groups or cationic groups (or both) could be polysaccharides, synthetic or semisynthetic polymers, polypeptides, proteins, salts, cellular and extracelluar materials.
The polysaccharides (and derivatives thereof) used according to the invention may be selected from polysaccharides such as cellulose derivatives such as CMC or derivatives thereof, chitin/chitosan or derivatives thereof, starches or derivatives thereof, alginates, pectin/pectat, gallan, hyaluronic acid or salts thereof, ionic derivatives of glucans, carragenans, glycomannan, xanthan, guar or derivatives thereof or locust bean gum, glucosamines, glucosaminoglycans such as heparan sulphate, chondroitin sulphate or keratan sulphate, and proteins and polypeptides such as heparin or collagen.
The hydrophilic polymer or material used according to this embodiment of the invention preferably comprises at least two of the following polysaccharides chitin/chitosan or their derivatives thereof, calcium/sodium alginate, pectin/pectate, carragenan, CMC, other derivatives of cellulose, hyaloronic acid, derivatives of starches and/or chondroitin sulphate.
The polymers used according to the invention preferably have an overall ionic charge in an aqueous solution.
In another preferred embodiment of the invention, the material can be made of only one hydrophilic polymer (or optionally more). The polymers to be used in this embodiment of the invention is(are) preferably selected from polysaccharides and derivatives thereof such as CMC, hydroxyethylcellulose, chitin/chitosan and alginates.
A preferred hydrophilic component is CMC or a mixture of CMC and an alginate or chitosan or its derivatives.
It is especially preferred that the polysaccharides comprises CMC and alginate in the form of a sodium alginate or a mixture of sodium and calcium alginates.
Furthermore, it is especially preferred according to the invention that the polysaccharide is chitosan.
In accordance with another aspect of the invention the solution to be frozen may essentially be based on pharmaceutical medicaments or a mixture of the hydrophilic polymers mentioned earlier in the description and pharmaceutical medicaments. Suitable pharmaceutical medicaments are, for example, a cytochine such as a growth hormone or a polypeptide growth factor such as TGF, FGF, PDGF, EGF, IGF-1, IGF-2, colony stimulating factor, transforming growth factor, nerve stimulating growth factor and the like.
Further suitable additives present in the solution to be frozen are cell lysates preferably from keranocytes or fibroblasts.
A growth hormone or a polypeptide growth factor shows an enhancing effect on wound healing.
It is also advantageous that a dressing according to the invention comprises wound healing associated indicator(s), cushions or similar device for treatment or prophylaxis of formation of wounds and/or skin anormalities.
This enables for a combined medical treatment of the wound and an easy and sterile application of the active ingredients, e.g., by incorporating active ingredients such as a cytochine such as growth hormone or a polypeptide growth factor giving rise to the incorporation of such active substances in a form being apt to local application in a wound in which the medicament may exercise its effect on the wound, other medicaments such as bacteriostatic or bactericidal compounds, e.g., iodine, iodopovidone complexes, chloramine, chlorohexidine, silver salts such as sulphadiazine, silver nitrate, silver acetate, silver lactate, silver sulphate or silver chloride, zinc or salts thereof, metronidazol, sulpha drugs, and penicillins, tissue-healing enhancing agents, e.g., RGD tripeptides and the like, proteins, amino acids such as taurine, vitamins such ascorbic acid, enzymes for cleansing of wounds, e.g., pepsin, trypsin and the like, proteinase inhibitors or metalloproteinase inhibitors such as Illostat or ethylene diamine tetraacetic acid, cytotoxic agents and proliferation inhibitors for use in, for example, surgical insertion of the product in cancer tissue and/or other therapeutic agents which optionally may be used for topical application, pain relieving agents such as lidocaine or chinchocaine, emollients, retinoids or agents having a cooling effect which is also considered an aspect of the invention.
In a second aspect, the invention relates to a non-fibrous porous material being swellable but not soluble in water.
The material comprises two or more hydrophilic polymers and optionally pharmaceutical medicaments. When the polymers are dissolved, they must have opposite charges in the solutions.
In a third aspect, the invention relates to a non-fibrous porous material whenever prepared by the method of the invention.
In a fourth aspect, the invention relates to a dressing comprising a non-fibrous porous material essentially consisting of one or more hydrophilic polymers or one or more hydrophilic polymers and one or more pharmaceutical medicaments, the material being producible by the method of the invention.
In a fifth aspect, the invention relates to the use of a non-fibrous porous material essentially consisting of one or more hydrophilic polymers or one or more hydrophilic polymers and one or more pharmaceutical medicaments wherein the porous material has been subjected to dry heat treatment for the preparation of a dressing or an absorbent article such as a wound dressings, an article for preventing post surgery adhesion or for haemostasis, disposable diapers, incontinence articles, sanitary napkins and the like having absorbent cores. This material may constitute a part of a product or be the product itself.
The term xe2x80x9csol gelxe2x80x9d is used in the present context to designate an aqueous dispersion of hydrated crosslinked particles. The particles act like independent particlesxe2x80x94not inter-cross-linked. The crosslinking bonds are either covalent or ionic. The liquid phase comprises pure water or an aqueous solution.
The term xe2x80x9cXerogelxe2x80x9d is used in the present context to designate a porous hydrophilic material having any desired shape and any desired internal morphology comprising a dry (dehydrated) porous matrix stretching throughout the material. A xerogel may be a water disintegrating or a water insoluble xerogel. A primary crosslinked xerogel is a disintegrating gel because it is prepared by dehydration of a sol gel and/or a polymer solution. Hence, it consists of independent polymer chains or dry sol gel particles. A secondary crosslinked xerogel is water absorbing but water insoluble because the dry sol gel particles are inter-crosslinked the building blocks of the cell walls are crosslinked to each other. Thus, such a gel forms a cohesive gel when soaked with water.
In the present context growth hormone is intended to designate any growth hormone which is applicable in accordance with the invention such as human, bovine, ovine, porcine, equine, salmon or tuna growth hormone or analogues or derivatives thereof such as shortened or extended growth hormones such as methionyl growth hormone. A growth hormone is preferably human growth hormone.
The invention is explained more in detail with reference to the below working examples disclosing embodiments of the invention which are to be considered illustrative only of principles of the invention. As all suitable modifications and equivalents may be resorted to, the examples are not to be considered as limiting the scope of the invention set forth in the appended claims.
Experimental Part